The objective of The University of Texas M. D. Anderson Cancer Center (UTMDACC) SPORE in Brain Cancer is to develop a robust translational research program with an emphasis on innovative treatments based on combinations of agents, molecularly-based diagnosis, and therapy monitoring, through which significant impact on the care of patients with malignant brain tumors will be achieved. UTMDACC has established the elimination of brain tumors as a priority and has made significant investments in this goal through establishment of a Brain Tumor Center and a Multidisciplinary Research Program to support training and research across several departmental boundaries, including neuro-oncology, neuro-surgery, neuro-pathology, diagnostic imaging, radiation oncology, epidemiology, molecular therapeutics, molecular genetics, molecular biology, pediatrics, and statistics. With this support, we have successfully organized an efficient and productive infrastructure that forms the basis for this SPORE. The translational research in this application is based on recent insights into the molecular basis of brain tumors and aims to translate these findings into innovative approaches to improve molecular diagnosis so that patients receive the therapy most likely to be benefit them, permit early evaluation of response to targeted treatment, and establish new and effective treatments based on oncolytic viruses and small molecule signal transduction inhibitors. The focus of the four Projects is described below: Project 1: Test a targeted oncolytic adenovirus, Delta-24-RGD in the clinic, and improve it by combining it with temozolomide and by delivery with mesenchymal stem cells. Project 2: Test PI3K inhibitor PX-866 in the clinic and develop rational combination therapies based on it. Project 3: Develop a molecular biomarker panel capable of identifying patients not likely to benefit from standard therapy, test it in the RTOG-0525 clinical trial with over 800 patients, and identify novel targets in the treatment of resistant tumors to support new therapy development. Project 4: Explore genetic predictors of neurocognitive and clinical outcome in glioblastoma patients. Five Cores (Administrative, Pathology and Tissue Procurement, Biostatistics, Clinical and Animal) will support the Projects, Career Development Program, and Developmental Research Program. It is imperative that we aggressively undertake translational research, as is embodied in this proposal to develop more effective approaches for patients with brain cancer; there are no effective treatment approaches for this patient population, and this SPORE guarantees that all of the resources of the UTMDACC Brain Tumor Research Program, as well as the considerable resources of the entire institution, will be brought to bear on this important public health problem.